The primary goal of this proposal is to characterize the physiological role of the interferon (IFN) regulatory factor-5 (IRF-5) transcription factor in the pathogenesis of systemic lupus erythematosus (SLE). SLE is a chronic systemic autoimmune disease that affects about 0.1% of the US population, and results in inflammation and damage to a range of organ systems. While the primary cause of SLE has not been determined, viral infection or dysfunction of the immune system has been suggested. Several lines of evidence have linked innate immune responses with the pathogenesis of SLE. Plasmacytoid dendritic cells (PDCs) are key mediators of innate immune responses, particularly via their ability to secrete cytokines. They are also the primary source of type I IFN, a molecule important in the front-line defense against viral infection, and recent data suggest that IFN produced by PDCs might be important for SLE pathogenesis. Type I IFNs are remarkable in their ability to prime further IFN production, which is likely to occur through the IFN regulatory factors, such as IRF-3, IRF-5, and IRF-7. Recent data indicate that polymorphism within the IRF-5 gene is associated with SLE; single-nucleotide polymorphisms (SNPs) were identified in the IRF-5 gene that displayed strong signals in joint analysis of linkage and association with SLE. IRF-5 is constitutively expressed mainly in cells of the immune system, particularly in PDC, monocytes, monocytederived dendritic cells, as well as in B cells. With the recent identification of multiple alternatively spliced IRF- 5 isoforms, each with distinct cell type-specific expression, regulation, and function, it is reasonable to suggest that polymorphism within IRF-5 may affect several cellular functions of importance for the development of an autoimmune disease such as SLE. As such, we hypothesize that alterations in IRF-5 isoform expression and function play an important role in SLE pathogenesis associated with the elevated levels of type I IFNs in the serum of SLE patients. The following specific aims have been designed to test this hypothesis, 1) Characterization of IRF-5 isoform expression associated with the pathogenesis of SLE, and 2) Determination of the physiological significance of IRF-5 polymorphism associated with SLE. Results from these studies will provide new insight into our understanding the physiological role for IRF-5 in the autoimmune and pathological phenomena of SLE. [unreadable] [unreadable] [unreadable] [unreadable]